MARKERS OF SUSCEPTIBILITY AS PREDICTORS OF BLADDER CANCER RECURRENCE We plan to build upon the epidemiologic and genetic findings and the existing specimen and data repository from the initial SPORE project and our funded research to evaluate predictors of bladder cancer (BC) recurrence in 800 patients with superficial BC. We have previously identified several promising markers in pathways for tobacco carcinogen activation/detoxification and DMA damage/repair. Now we propose to extend our candidate gene approach to a pathway-based approach to systematically examine the joint influence of genetic polymorphisms in specific pathways on clinical outcome;to extend our panel from metabolism and DMA damage/repair pathways to inflammation, oxidative stress, and the TRAIL-induced apoptosis pathways;to integrate clinical and epidemiologic data with the genetic data to build a quantitative risk assessment model for BC recurrence;to link our research to an ongoing BCG clinical trial on superficial BC;and finally to explore functional significance of the SNPs. Our specific aims are as follows: (1). 1a. Construct a well-characterized cohort of 800 patients with superficial BC;1b. Assess frequencies of genetic predisposition markers in all 800 cases including SNPs in genes that are involved in inflammatory processes, oxidative stress, and TRAIL induced apoptosis. Our hypothesis is that polymorphisms in these genes are associated with risk of BC recurrence, and may also have effects on BCG treatment response in patients with superficial BC. 1c. Build up risk assessment model for BC recurrence. We will integrate clinical and epidemiologic data with the genetic data from the studies described above as well as from the initial grants to build a quantitative risk assessment model for BC recurrence. Genetic variations on metabolic enzyme genes, microenvironment genes, and DNA repair genes will be available from our other funding sources to be incorporated into the model. (2). Assess determinants of BCG treatment response in 200 patients with superficial BC enrolled in a clinical trial. We will measure protein levels of IL-2, IL-8, and TRAIL in voided urine specimens. We will correlate these protein levels as well as SNPs in pathways relevant to the the action of BCG (especially genes involved in inflammation, oxidative stress, and TRAIL apoptosis pathways with recurrence rates. Our hypothesis is that specific genotypes in genes related to the mechanism of BCG action may negatively affect the treatment response of patients with BC to this therapy. As a secondary aim, we will use experimental approaches and/or computational approaches to verify or discover the functional impact of promising polymorphisms. Our hypothesis is that SNPs associated with bladder cancer recurrence alter the function of their genes. The ability to rapidly screen individuals for BC recurrence risk using minimally invasive procedures (blood and urine samples) has immense clinical value. These markers will be useful for identifying patient subgroups at high risk for recurrence who should undergo more intensive screening. Markers of treatment response could be used to design individualized treatment plans.